CN103405437A - PI3K small-molecule inhibitor and application thereof - Google Patents
PI3K small-molecule inhibitor and application thereof Download PDFInfo
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- CN103405437A CN103405437A CN2013103873486A CN201310387348A CN103405437A CN 103405437 A CN103405437 A CN 103405437A CN 2013103873486 A CN2013103873486 A CN 2013103873486A CN 201310387348 A CN201310387348 A CN 201310387348A CN 103405437 A CN103405437 A CN 103405437A
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Abstract
The invention discloses a PI3K small-molecule inhibitor and an application thereof. The inhibitor is 5-[3-(2-thiophene)-2-propene-1-] 2, 4, 6 (1H, 3H, 5H)-barbituric acid and has the functions of effectively inhibiting the propagation of various tumor cells and inducing the apoptosis of the tumor cells. The PI3K small-molecule inhibitor newly developed by the invention has low toxicity for normal cells and has a remarkable inhibiting effect on the phosphorylation of AKT (Threonine Kinase) induced by PI3K and the activation of an AKT downstream protein, so that the propagation of the various tumor cells can be effectively inhibited, the apoptosis of the tumor cells can be induced, and furthermore, the PI3K small-molecule inhibitor is expected to be developed into a novel anti-tumor drug. The PI3K small-molecule inhibitor has in-vitro and in-vivo therapeutic effects for various tumors such as acute and chronic leukemia, multiple myeloma, lymphoma and the like.
Description
Technical field
The invention belongs to the pharmaceutical chemistry field, relate to the PI3K inhibitor, be specifically related to a kind of PI3K micromolecular inhibitor and application thereof.
Background technology
Cancer is still one of main cause of the death of the mankind at present.Clinician and scientists all are being devoted to the improvement of tumor therapeuticing method, as improve surgical operation skill, refine X-ray therapy, the new chemicals of research and development, although these effort are all beneficial for the treatment development of cancer, but at present the treatment of tumor still has very large development space, finds novel low toxicity efficiently and the antitumor drug of high specific is the important directions that life scientists are studied.
Phosphatidylinositol-3-kinase (phosphatidylinositol 3-kinase, be called for short PI3K) be a kind of conclusive kinases that affects multiple path, these paths can be regulated cell enlargement, the cell activities such as apoptosis and survival, especially the PI3K of I type, comprise a P85 and regulate subunit and P110 catalytic subunit, in these cell activities, all play an important role, in a single day PI3K is activated, will phosphorylation AKT(protein kinase B), the AKT be activated will activate successively and regulate the GSK that protein is transcribed, P70S6k, 4EBP1, and the P27 that regulates cell cycle, P21, cMyc, cyclinD1 etc., in addition, the AKT be activated can act on mitochondrial protein as apoptosis-induced as Bad etc. and anti-apoptosis equally.
Recently research finds, the PI3K signal path is the signal path of modal allosome sudden change in the human tumor cell, and the excessive activation of this signal path and the generation of tumor, development, prognosis are closely related, inhibition PI3K activity, and apoptosis appears in cancerous cell; Suppress the PI3K signal and can overcome the chemical drug resistance of kinds of tumors such as comprising leukemia, lymphoma, multiple myeloma, more and more more be subject to people's attention as the research and development of the antitumor drug of target spot so take PI3K.Also positive exploitation is as the compound of target spot for domestic and international many pharmaceuticals and scientific research institution, and what have has entered clinical trial.
Chemical compound lot can suppress the conduction of PI3K signal although reported in prior art, exists pharmaceutically active too strong, large and unstable in water to normal cytotoxicity, limits the shortcoming of its application.Therefore need a kind of new low molecular organic depressant of research, can obvious inhibitory action be arranged to the PI3K signal path, thus the effective antitumour medicine that exploitation makes new advances.
Summary of the invention
Goal of the invention of the present invention is to provide a kind of PI3K micromolecular inhibitor, and described inhibitor has the propagation that can suppress kinds of tumor cells, and induces the function of its apoptosis.
To achieve the above object of the invention, the technical solution used in the present invention is: a kind of PI3K micromolecular inhibitor, and described inhibitor is expressed by the following chemical structure formula:
The chemical name of PI3K micromolecular inhibitor disclosed by the invention is 5-[3-(2-thiophene)-2-propylene-1-] 2,4,6 (1H, 3H, 5H)-barbituratess, be called C96.
The present invention protects the application of above-mentioned PI3K micromolecular inhibitor in preparing antitumor drug simultaneously.
Preferably, described tumor is following any: leukemia, myeloma, lymphoma.
Principle of the present invention is: the new PI3K micromolecular inhibitor of the present invention's exploitation is mainly by suppressing the PI3K/AKT signal path, and then the expression of inhibition cyclin, suppress the phosphorylation of AKT and suppress the carrying out of cell cycle, thus the effective propagation of inhibition tumor cell; And its apoptosis of active cell apoptosis enzyme induction.
The present invention is claimed a kind of antineoplastic pharmaceutical compositions simultaneously, and the active component of described antitumor drug is above-mentioned PI3K micromolecular inhibitor, also comprises pharmaceutically receptible carrier or adjuvant.
PI3K micromolecular inhibitor of the present invention can be made the preparation administration separately or with more than one acceptable carrier combination agent.For example, solvent, diluent etc.Can the peroral dosage form administration, but as tablet, capsule dispersed powders, granule etc.; Also can the injection-type administration, as lyophilized injectable powder.The various dosage forms of pharmaceutical composition of the present invention can be prepared according to the method for knowing in pharmaceutical field.In these pharmaceutical formulations, can contain for example 0.05%～90% weight active component with carrier combinations, the more common approximately active component between 15%～60%.The compounds of this invention dosage can make 0.005～5000mg/kg/ days, also can exceed this dosage range according to the different using dosages of disease severity or dosage form.
Because technique scheme is used, the present invention compared with prior art has following advantages:
1. the present invention prepares the PI3K micromolecular inhibitor by area of computer aided drug screening and the method that mutually combines biology, reacts simple to operation, and product is easily purified, yield is high, stable;
2. the PI3K signal path micromolecular inhibitor researched and developed of the present invention is low to normal cytotoxicity, and the AKT phosphorylation that PI3K is induced, the activation of AKT downstream albumen have significant inhibitory action, therefore can effectively suppress kinds of tumor cells propagation, inducing apoptosis of tumour cell, thereby be expected to it is developed to new antitumor drug.
The accompanying drawing explanation
Fig. 1 is the design sketch that in embodiment bis-, Compound C 96 suppresses the multiple myeloma cells growth;
Fig. 2 is the design sketch that in embodiment bis-, Compound C 96 suppresses leukaemia's growth;
Fig. 3 is the design sketch that in embodiment tri-, Compound C 96 is induced the multiple myeloma apoptosis;
Fig. 4 is the design sketch that in embodiment tri-, Compound C 96 is induced the multiple myeloma apoptosis;
Fig. 5 is the design sketch of inducing of the activation of 96 pairs of multiple multiple myeloma cells apoptosis enzymes of Compound C in embodiment tetra-;
Fig. 6 be 96 pairs of multiple myeloma cells apoptosis enzymes of Compound C in embodiment tetra-activation induce the design sketch with the compound concentration relation;
Fig. 7 be 96 pairs of multiple myeloma cells apoptosis enzymes of Compound C in embodiment tetra-activation induce the design sketch with the compound effects time relationship;
Fig. 8 is 96 pairs of inhibitory action by the P-AKT of ICF I stimulation of Compound C in embodiment five;
Fig. 9 is P-AKT inhibitory action that in embodiment five, 96 pairs of Compound C are stimulated by the ICF I and the design sketch of compound concentration;
Figure 10 is the inhibitory action of the P-AKT that in embodiment five, 96 pairs of Compound C are stimulated by the ICF I and the design sketch of action time;
Figure 11 is that in embodiment five, 96 couples of P-AKT that stimulated by the ICF I of Compound C transfer to the inhibitory action on cell membrane;
Figure 12 is the action effect figure of 96 pairs of PI3K-AKT-mTOR signal path downstream associated protein of Compound C in embodiment six;
Figure 13 is the action effect figure of Compound C 96 to other pathway associated proteins in embodiment six;
Figure 14 is the gross tumor volume comparison diagram of administration group and matched group in heteroplastic transplantation experiment in embodiment seven;
Figure 15 is the Mouse Weight comparison diagram of administration group and matched group in heteroplastic transplantation experiment in embodiment seven;
Figure 16 is in embodiment seven in heteroplastic transplantation experiment, the inhibitory action figure of 96 pairs of AKT phosphoric acid activations of Compound C.
The specific embodiment
The invention will be further described below in conjunction with embodiment:
Embodiment mono-: 5-[3-(2-thiophene)-2-propylene-1-] 2,4,6 (1H, 3H, 5H)-barbituratess (C96) synthetic
General line:
Concrete each step reaction:
By compound
1(500mg, 4.46mmol, 1eq), malonic acid (695.9mg, 6.69mol, 1.5eq), morpholine (38.8mg, 0.45mmol, 0.1eq), be dissolved in the pyridine of 5mL, 80 ℃ of back flow reaction 24h, reactant liquor dilutes with dichloromethane (DCM), 1M hydrochloric acid (HCl) washing, organic facies anhydrous sodium sulfate (NaSO
4) drying, concentrated, column chromatography (DCM+0.5% acetic acid (HAc)), obtain compound
4For faint yellow solid 634.0mg (92%);
1H NMR (400 MHz, CDCl
3) δ 10.75 (s, 1H), 7.89 (d,
J=15.6 Hz, 1H), 7.43 (d,
J=4.9 Hz, 1H), 7.30 (s, 1H), 7.08 (t,
J=4.0 Hz, 1H), 6.25 (d,
J=15.6 Hz, 1H).
By compound
4(20mg, 0.13mmol, 1.0eq) is dissolved in 0.5ml methanol (MeOH), splashes into two thionyl chloride (SOCl
2) stirred overnight at room temperature, after having reacted, revolve to steam and remove methanol and thionyl chloride, obtain the faint yellow solid compound
5, 21mg (100%).
By compound
5(38.2mg, 0.23mmol, 1.0eq) joins in anhydrous tetrahydro furan (THF), under-78 ℃ of conditions, slowly splashes into DIBAL-H (31.1mg, 0.27mmol, 1.2eq), adds the shrend reaction of going out, ethyl acetate (EA) extraction, anhydrous Na SO
4Drying, column chromatography purification obtains compound
6For faint yellow oily thing 21.3mg (66.9%), place the rear one-tenth solid that spends the night;
1H NMR (400 MHz, CDCl
3) δ 7.16 (d,
J=2.4 Hz, 1H), 6.96 (d,
J=2.9 Hz, 2H), 6.74 (d,
J=15.7 Hz, 1H), 6.20 (dt,
J=15.7,5.8 Hz, 1H), 4.28 (dd,
J=5.7,1.1 Hz, 2H).
Prepare active MnO
2
By 9.6gKMnO
4Be dissolved in 60mL water, reflux, slowly add under stirring and contain 5g MnSO
4 .H
2The 15mL aqueous solution of O, 40% sodium hydroxide (NaOH) solution 11.7mL, the about 1h of insulated and stirred reaction; Through the buchner funnel sucking filtration, filter cake washes with water by reactant liquor, until eluate is water white transparency, the filter cake oven drying, obtain brown ceramic powder 5g, is active MnO
2, powder is evenly fine and smooth, can be used for the subsequent oxidation reaction.
By compound
6(21.3mg, 0.15mmol, 1.0eq), add compound
6The active MnO of 8 equivalents
2, stirring at room is after a period of time, and reacting liquid filtering, use the DCM washing leaching cake, and the filtrate concentrated by rotary evaporation, obtain compound
7For yellow oil 16.4mg (84%);
1H NMR (400 MHz, CDCl
3) δ 9.62 (d,
J=7.7 Hz, 1H), 7.58 (d,
J=15.6 Hz, 1H), 7.50 (d,
J=4.9 Hz, 1H), 7.36 (d,
J=2.9 Hz, 1H), 7.11 (t,
J=4.2 Hz, 1H), 6.51 (dd,
J=15.6,7.7 Hz, 1H).
By compound
7(barbiturates joins grease to (100mg, 0.724mmol, 1eq) and barbiturates (92.6mg, 0.724mmol, 1eq) mix homogeneously
7In, add 5 milliliters of ethyl acetate, then ethyl acetate be spin-dried for, obtain 8 and the homogeneous mixture of barbiturates), this mixture is put to microwave oven microwave reaction (the fiery 2min of middle height * 3); After having reacted, add ether in system, mix rear filtration, then, with ether washing three times, with hot wash for several times, clarify to eluate, filter cake is dry under infrared lamp, obtains Chinese red solid C96,89 mg (38.3%);
1H NMR (400 MHz, DMSO) δ 11.23 (s, 1H), 11.18 (s, 1H), 8.17 (dd,
J=15.0,12.0 Hz, 1H), 7.97 (d,
J=11.9 Hz, 1H), 7.91 (d,
J=15.2 Hz, 1H), 7.86 (d,
J=4.9 Hz, 1H), 7.52 (d,
J=3.2 Hz, 1H), 7.21 (dd,
J=4.9,3.8 Hz, 1H).
Embodiment bis-C96 suppress multiple myeloma cells and leukaemia's growth
Cultivate multiple multiple myeloma cells (LP1, RPMI-8226, U266, OPM2, KMS11, OCI-MY5, JJN3 cell) and leukaemia's (THP1, K562, AML2, NB4OCI-MY5, cell), with the C96 of variable concentrations, process 72h, by MTS/PMS staining analysis of cells survival rate.
Accompanying drawing 1 suppresses the design sketch of multiple myeloma cells growth for C96, result shows that C96 presents concentration dependent to the inhibitory action of multiple myeloma propagation; Accompanying drawing 2 is that C96 suppresses the design sketch of leukaemia's growth, and result shows that C96 presents concentration dependent to the inhibitory action of Leukemia Cell Proliferation, and the inhibitory action of Leukemia Cell Proliferation is presented to concentration dependent.Reach a conclusion thus: C96 can effectively suppress multiple myeloma and leukaemia's growth.
Embodiment tri-C96 induce the apoptosis of multiple myeloma cells
Cultivate LP1, OPM2, OCI-MY5, KMS11, RPMI-8226, JJN3 cell, process 24h with variable concentrations C96, collecting cell, with Annexin V-FITC with PI is two dyes, with flow cytometer detection Annexin V
+The ratio that cell is shared.
Accompanying drawing 3,4 is induced the design sketch of multiple myeloma apoptosis for C96, result shows: C96 can effectively induce the apoptosis of multiple myeloma, and apoptosis rate and C96 present concentration dependent.
Embodiment tetra-C96 activate the apoptosis of tumor cells enzyme
By multiple myeloma cell line cell LP1, OPM2, U266, KMS11, RPMI-8226, OCI-MY5 cell, through variable concentrations C96, processed 24 hours, with the SDS protein lysate cracking that contains positive vanadium sodium, after quantification of protein, get 30mg albumen and carry out gel electrophoresis, detect the expression of PARP, caspase3, with GAPDH or actin as internal reference.
Accompanying drawing 5, for the design sketch of inducing of C96 to the activation of multiple multiple myeloma cells apoptosis enzyme, can prove that C96 can effectively induce the apoptosis of multiple myeloma; Accompanying drawing 6 is that C96 is to the inducing action of the apoptotic proteins enzyme of LP1, OPM2, JJN3 cell and the relation of drug level, can find out that Pro-Caspase3 descends gradually with the rising of C96 concentration, and Cle-Caspase3 rises gradually along with the rising of C96 concentration, identical phenomenon also appears in PARP; Accompanying drawing 7 is that C96 is to the inducing action of the apoptotic proteins enzyme of LP1, OPM2, JJN3 cell and the relation of action time.In conjunction with Fig. 6,7, show that C96 can effectively induce the apoptotic proteins enzyme of multiple myeloma, and this inducing action and C96 present concentration and time dependence.
Embodiment five C96 suppress the AKT activation
By multiple myeloma cells LP1, OPM2, OCI-MY5, JJN3 cell, low serum overnight (0.5%) is cultivated, after medicine (C96 or DMSO) is processed 2 hours with IGFI effect 15min, collecting cell, with the SDS protein lysate that contains positive vanadium sodium, extract total protein, with Western blot, detect the expression of phosphorylation p-AKT and total AKT, GAPDH is as internal reference.
Accompanying drawing 8 is the inhibitory action of C96 to the P-AKT by the stimulation of ICF I, and result shows that C96 can effectively suppress the AKT phosphorylation; Accompanying drawing 9, accompanying drawing 10 are respectively P-AKT inhibitory action and the relation of compound concentration and action time of C96 to being stimulated by the ICF I, can find out that C96 presents the dependency of action time and concentration to the inhibition of the P-AKT by the stimulation of ICF I.
Further with C96, process the OPM2 cell of cultivating, with specificity p-AKT, AKT antibody, make immunofluorescence analysis, utilize Laser Scanning Confocal Microscope to take immunofluorescence image, accompanying drawing 11 is transferred to the inhibitory action on cell membrane for C96 to the P-AKT stimulated by the ICF I, result shows that C96 can suppress p-AKT, and can suppress its gathering to cell membrane.
Embodiment six C96 act on the associated protein in AKT downstream
By multiple myeloma cell line cell LP1, OPM2, JJN3 cell, through variable concentrations C96, processed 24 hours, with the SDS protein lysate cracking that contains positive vanadium sodium, get 30mg albumen and carry out gel electrophoresis, detect the expression of associated protein, GAPDH is as internal reference.
Accompanying drawing 12,13 is respectively the action effect figure of C96 to PI3K-AKT-mTOR signal path downstream associated protein and other pathway associated proteins; Can find out that C96 can make the downstream associated protein of AKT such as p-mTOR, mTOR, p-P70S6K, P70S6K, the corresponding minimizing of p-4E-BP1,4E-BP1, also can make p-FOXO1 (FOXO3), the corresponding minimizing of BCL-2, p-GSK (ser9), along with the concentration of C96 raises and rises.
Embodiment seven C96 suppress the growth of multiple myeloma and suppress AKT phosphorylation in its body in mice multiple myeloma model
Myeloma cell strain JJN3 subcutaneous injection, reach can touch the time until tumor tissues, and random packet, be divided into matched group and administration group, starts administration (100mg/kg/day), continuous 16 days.Measure every other day tumor size, weighing every day Mouse Weight, accompanying drawing 14 are the gross tumor volume comparison diagram of administration group and matched group in above-mentioned heteroplastic transplantation experiment; Accompanying drawing 15 is the Mouse Weight comparison diagram of administration group and matched group in above-mentioned heteroplastic transplantation experiment; Result show C96 can effectively suppress tumor growth but on the not significantly impact of the body weight of mice.
The tumor of laboratory animal is taken out, advance to shred, add the ultrasonication of lysate income, then the centrifuging and taking supernatant, get 30mg albumen and carry out gel electrophoresis, detects the expression of PARP, caspase3, GAPDH is as internal reference, accompanying drawing 16 is in above-mentioned heteroplastic transplantation experiment, and the inhibitory action of 96 pairs of AKT phosphoric acid activations of Compound C shows that C96 can effectively suppress the AKT phosphorylation in the animal tumor tissue.
Claims (4)
1. a PI3K micromolecular inhibitor, is characterized in that, described inhibitor is expressed by the following chemical structure formula:
2. the application of PI3K micromolecular inhibitor claimed in claim 1 in preparing antitumor drug.
3. application according to claim 2 is characterized in that: described tumor is following any: leukemia, myeloma, lymphoma.
4. antineoplastic pharmaceutical compositions, it is characterized in that: the active component of described antitumor drug is the described PI3K micromolecular inhibitor of claim 1, also comprises pharmaceutically receptible carrier or adjuvant.
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|---|---|---|---|---|
| CN103951640A (en) * | 2014-05-08 | 2014-07-30 | 苏州大学 | Compound and preparation method and application thereof |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102690238A (en) * | 2011-03-21 | 2012-09-26 | 华东理工大学 | Synthesis of barbituric acid derivative as RSK2 inhibitor and application thereof |
| WO2013024447A1 (en) * | 2011-08-18 | 2013-02-21 | Nuhope, Llc | Compounds for use in cancer therapy |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102690238A (en) * | 2011-03-21 | 2012-09-26 | 华东理工大学 | Synthesis of barbituric acid derivative as RSK2 inhibitor and application thereof |
| WO2013024447A1 (en) * | 2011-08-18 | 2013-02-21 | Nuhope, Llc | Compounds for use in cancer therapy |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN103951640A (en) * | 2014-05-08 | 2014-07-30 | 苏州大学 | Compound and preparation method and application thereof |
| CN103951640B (en) * | 2014-05-08 | 2016-03-02 | 苏州大学 | A kind of compound and preparation thereof and purposes |
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